title: Thiazolylaminomannosides as potent antiadhesives of type 1 piliated Escherichia coli isolated from Crohn's disease patients.
abstract: Adherent-invasive Escherichia coli (AIEC) have previously been shown to induce gut inflammation in patients with Crohn's disease (CD). We developed a set of mannosides to prevent AIEC attachment to the gut by blocking the FimH bacterial adhesin. The crystal structure of the FimH lectin domain in complex with a lead thiazolylaminomannoside highlighted the preferential position for pharmacomodulations. A small library of analogues showing nanomolar affinity for FimH was then developed. Notably, AIEC attachment to intestinal cells was efficiently prevented by the most active compound and at around 10000-fold and 100-fold lower concentrations than mannose and the potent FimH inhibitor heptylmannoside, respectively. An ex vivo assay performed on the colonic tissue of a transgenic mouse model of CD confirmed this antiadhesive potential. Given the key role of AIEC in the chronic intestinal inflammation of CD patients, these results suggest a potential antiadhesive treatment with the FimH inhibitors developed.
authors.affiliation: LUNAM Université , CEISAM, Chimie Et Interdisciplinarité, Synthèse, Analyse, Modélisation, UMR CNRS 6230, UFR des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 NANTES Cedex 3, France.
authors.forename: Sami
authors.initials: S
authors.lastname: Brument
authors.forename: Adeline
authors.initials: A
authors.lastname: Sivignon
authors.forename: Tetiana I
authors.initials: TI
authors.lastname: Dumych
authors.forename: Nicolas
authors.initials: N
authors.lastname: Moreau
authors.forename: Goedele
authors.initials: G
authors.lastname: Roos
authors.forename: Yann
authors.initials: Y
authors.lastname: Guérardel
authors.forename: Thibaut
authors.initials: T
authors.lastname: Chalopin
authors.forename: David
authors.initials: D
authors.lastname: Deniaud
authors.forename: Rostyslav O
authors.initials: RO
authors.lastname: Bilyy
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.forename: Julie
authors.initials: J
authors.lastname: Bouckaert
authors.forename: Sébastien G
authors.initials: SG
authors.lastname: Gouin
mesh_terms: D018830:Adhesins, Escherichia coli / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001422:Bacterial Adhesion / Q000187:drug effects*; D001665:Binding Sites; D018938:Caco-2 Cells; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D003424:Crohn Disease / Q000382:microbiology*; D004926:Escherichia coli / Q000378:metabolism / Q000502:physiology*; D036781:Fimbriae Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000502:physiology; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007422:Intestines / Q000187:drug effects / Q000382:microbiology; D019169:Jurkat Cells; D008362:Mannosides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008956:Models, Chemical; D015394:Molecular Structure; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018830:Adhesins, Escherichia coli; D015703:Antigens, CD; C504117:CEACAM6 protein, human; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D008362:Mannosides; D013844:Thiazoles; C058769:fimH protein, E coli; D036781:Fimbriae Proteins